[CIS PIDD] [cis-pidd] Hyper IgM syndrome?

[CIS-PIDD]

Dear colleagues,

I am writing to ask you for your opinion about a challenging case.

Our patient is a 14yo boy who was healthy until the age of 9yo when he had two episodes of ITP episodes treated with steroids, IVIG, and rituximab.  Then this year, he was hospitalized for fever with ITP, Coombs+ anemia, weight loss, pulmonary nodules on chest CT, and significant splenomegaly.  He was treated with IV antibiotics, and slowly improved, without any immuno suppression.  Immunoglobulin levels demonstrated IgA <5, IgG <25, IgM 1357 (last rituxtimab dose 4 years ago). Lymph node biopsy demonstrated follicular hyperplasia with predominant primary follicles (no polarization), and increased IgM+ lymohoplasmacytic cells.  No evidence of malignancy nor plasmactyosis.  BM biopsy demonstrated mildly hypo cellular marrow (70%) with active trilineage hematopoiesis.  Normal T cell, NK, and total B cell numbers, but decreased (close to zero) isotope switched B cells (CD19+CD38+IgM-, CD19+CD27+IgM-IgD-).  Normal Treg cell numbers (foxp3 stain).  Lymphocyte stimulation with normal mitogen and tetanus response (mildly decreased ConA, but otherwise normal). A battery of infectious studies all yielded negative results (EBV, CMV, bacterial cx, PCP, fungal cx, mycobacterial cx).  

WES sent at this point, and started on IgG replacement, with no other immunomodulator. Splenomegaly significantly improved, no fevers, normal CBC, still some fatigue, slowly regaining weight.   3 months later, repeat immunoglobulins demonstrate IgG 207, IgA<10, IgM 340.  WES results (GeneDx) demonstrate het mutations for PKLR (pyruvate kinase deficiency), VPS13B (Cohen syndrome), and ANK1 (hereditary spherocytosis).  Given his IgM has almost normalized with only IgG supplementation, this is unlikely HIGM I think. CD40/40L,UNG, AID, IKBa coverage was pretty good. NEMO coverage not so good (26%).  He however does not many any of the physical exam features, and does not have any GI issues.  None of the mutations founds are consistent with his phenotype, and they are only heterozygous.  

I’m facing a diagnostic dilemma at this point.  My original thought of HIGM seems to have gone out the window, any other suggestions?

Thanks,

Elena Hsieh, MD
Department of Immunology and Microbiology
Department of Pediatrics, Division of Allergy and Immunology
University of Colorado, Denver
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